Editor’s Note: About 30 percent of all
people suffering from depression do not respond adequately to available
treatments. Our author, a leading researcher in the field of
antidepressants, says that the rediscovery of a promising, yet problematic drug called ketamine
is the most significant breakthrough for treating depression in
half a century. Will ketamine inspire the next generation of antidepressants?

Source/Shutterstock

The World Health Organization reports that
depression is the leading cause of disability and loss of work worldwide,
affecting more than 300 million people.3 In the
United States, the lifetime incidence of major depressive disorder is
approximately 17 percent at an estimated cost to the economy of over $200 billion annually.1 This
devastating illness is characterized by depressed mood, feelings of
worthlessness, inability to experience pleasure, and disruption of eating,
sleeping, social, and sexual activities. In severe cases, it can lead to
suicide, which has become the third leading cause of death, up 30 percent over
the past 10 years, to more than 44,000 in the US alone.2

Despite its
prevalence and impact, the available therapeutic
medications for depression are limited to one class of drugs, monaminergic
agents that increase levels of serotonin and/or norepinephrine. These drugs
block the reuptake or metabolism of monoamines and, over time, lead to adaptive
changes that underlie their antidepressant actions. This class of
antidepressants was discovered in the 1950s, and although there have been
refinements to reduce side effects, they have gone largely unchanged in over 60
years. These agents have serious limitations, notably low rates of efficacy
(only one in three patients respond to the first prescribed medication), and a
delay in therapeutic response of weeks to months.4 Even after trying
multiple types of monoaminergic agents, plus supplemental medications, about a
third of patients remain nonresponsive and are considered treatment resistant.
The time lag and treatment resistance can have fatal consequences for a
population at high risk of suicide.

The
limitations of currently available agents explain the excitement and hope
surrounding the discovery of a new class of antidepressants whose prototype,
ketamine, produces rapid (within hours) relief from severe depressive symptoms,
even in patients considered treatment resistant.5 Ketamine is an
antagonist of the NMDA (N-methyl-D-aspartate) receptor, one type of receptor
for glutamate, the major excitatory amino acid in the brain.At high doses, the drug is used as a
dissociative anesthetic, producing catalepsy, catatonia, analgesia, and
amnesia, that is often used for pediatric and veterinary medicine. A single low
dose of ketamine, however, produces rapid antidepressant actions that last for
approximately one week in most individuals. The discovery of a new, rapidly
acting class of drug with a completely novel mechanism is arguably the biggest
breakthrough in the field of depression in over 60 years. However, ketamine
also has side effects, notably dissociative and psychotomimetic actions that,
while transient, have limited its widespread use.

Nevertheless,
the discovery of ketamine provides a much-needed option for treatment resistant
depression and has spurred research and drug development efforts to identify
new drugs that produce its rapid and efficacious antidepressant actions without
its side effects. Let’s explore the discovery and validation of ketamine as a
rapid acting antidepressant, its novel mechanism of action, and progress toward
the development of like agents.

Drug
Development Issues

The
monoamine reuptake blocking antidepressants, which include the serotonin
selective reuptake inhibitors that are among the most highly prescribed classes
of drugs, began with tricyclics antidepressants, an early chemical subclass
that blocks the reuptake of serotonin and norepinephrine. Patients given
tricyclics reported improvement in depressive symptoms, but only after the
drugs had been administered for several weeks. This led to the monoamine
hypothesis that deficits in serotonin or norepinephrine in the brain cause
depression, although the evidence for this theory is not very strong.

The
time lag for the therapeutic action of monoaminergic agents has also been
difficult to explain, since these agents rapidly block reuptake and increase synaptic levels of
monoamines in a matter of days. This
has led to the theory that delayed neuronal adaptation to elevated serotonin is
required for an antidepressant response. Among a number of reports on adaptive
changes, one key hypothesis attributes therapeutic action to delayed increase
in the expression of growth factors, particularly BDNF (brain-derived
neurotrophic factor). The elevation of BDNF contributes to the reversal of
synaptic deficits caused by chronic stress and depression.

While
these drugs provide some therapeutic benefit, their shortcomings have prompted
continuous research and development over the past decades. These efforts have
focused largely on refinements of monoamine reuptake inhibitors to reduce their
side effects, the creation of selective or dual reuptake inhibitors, and the
development of agents that target reuptake of dopamine, a monoamine
neurotransmitter system involved in motivation and reward. Most of these new
monoaminergic agents have the same limitations of the earlier ones, except a somewhat
better side effect profile. There have also been efforts to target blockade of
neuropeptides, notably corticotrophin releasing factor (CRF), that mediate the
endocrine and behavioral responses to stress. These are based on rational
design and significant antidepressant-like effects in rodent models, but have
not translated into effective treatment options for humans. More generally,
this difficulty in translation from experimental animals to patients has been a
serious problem for development of novel medications for all psychiatric
illnesses and the reason why most major pharmaceutical companies have
significantly or completely cut research and development is this area.

Figure 1. Preclinical
studies show evidence of neuronal atrophy and loss in response to stress.
Chronic stress, which can lead to depression, decreases synaptic connections in
the PFC and hippocampus.

Ketamine
and NMDA Receptor Antagonists

The
discovery of ketamine as a rapid antidepressant goes back to early attempts to
understand the neurobiology of psychosis and schizophrenia. A related compound,
phencyclidine (PCP), was first synthesized by Parke-Davis in 1959 and, although
it was a potent anesthetic, it produced severe hallucinations upon awakening.

Efforts
to circumvent this problem led to the synthesis of ketamine in 1962, which also
had potent anesthetic and analgesic properties, and was approved for clinical
use by 1970, although it still produced psychotomimetic actions, but less so
than PCP. (The psychotomimetic and dissociative effects these drugs produce at
low doses6 have led to their abuse; on the street, ketamine and PCP
are referred to as “special K” and “angel dust,” respectively.)

These
agents block NMDA receptors, a major class of excitatory neurotransmitter
receptors in the brain that gate the entry of calcium, an important signaling
molecule. When the NMDA receptor is activated by glutamate, the channel opens
to allow calcium to flow inside the neuron; in this open state ketamine can
also enter and bind inside the channel and block subsequent calcium entry and
NMDA receptor function. While these agents were found to produce anesthesia at
high doses, at low doses they were found to produce psychotomimetic and
dissociative effects in humans.6

Figure
2.

The
finding that NMDA receptor antagonists produce psychotomimetic effects
contributed to the NMDA receptor deficit hypothesis of schizophrenia, and
research efforts on the neurobiology of this illness included studies with low
doses of ketamine. In addition, evidence was accumulating that linked chronic
administration of typical antidepressants to adaptations of NMDA receptor
expression and function. Together these findings led John Krystal, Rob Berman,
Dennis Charney and colleagues at Yale University to test the antidepressant
actions of ketamine. In this small, double blind, placebo-controlled trial, a
single dose of ketamine was found to produce a rapid antidepressant response
with an average onset of four hours that lasted for at least three days.5
This therapeutic response occurred after approximately one to two hours of
transient, psychotomimetic, and dissociative effects. These studies used
intravenous administration, since that was the typical route used clinically
for anesthesia and received straightforward approval from the Health Insurance
Commission.

Surprisingly,
this important discovery was not pursued for several years, partly because of
negative press about ketamine research conducted in psychiatric patients,
particularly those with schizophrenia, and questions about the competency of
these patients to give informed consent. It wasn’t until six years later that
one of the original investigators, Dennis Charney, together with Carlos Zarate
and others at National Institute of Mental Health conducted a second, larger
double-blind placebo controlled trial that confirmed the original findings.7
This study described a more detailed time course, which demonstrated
significant therapeutic improvements as early as 80 minutes after a single dose
of ketamine, and that lasted for at least seven days.

There
have now been multiple research trials that confirm and validate the rapid and
efficacious actions of ketamine for the treatment of depression. There are
still some reservations, partly because it is difficult to account for
potential placebo effects since patients receiving ketamine know they have been
administered an active compound (due to the drug’s dissociative psychotomimetic
effects). Trials are now run with an active comparator, such as midazolam, a
short acting benzodiazepine that produces anxiolytic effects, but it is still
difficult to completely discount placebo effects because of the potent acute
behavioral effects of ketamine.

In
addition, recent trials demonstrate that ketamine is effective for suicidal
ideation, which is particularly difficult to treat with monoaminergic
antidepressants, and represents a second important potential therapeutic
indication for the drug. There have also been reports that ketamine has
efficacy for post-traumatic stress syndrome (PTSD), another difficult-to-treat
illness that responds poorly to currently available medications.

Work
in my laboratory has focused on the neurobiology of stress and depression, and
the mechanisms by which antidepressants produce a therapeutic response. At a
meeting where we described our work on typical monoaminergic antidepressants,
Charney showed us a video of a severely depressed patient who had failed to
respond to a typical antidepressant. The video was incredible in that this
chronically depressed patient displayed a dramatic improvement within a few
hours after receiving ketamine. In discussions afterwards, Charney suggested
that research was sorely needed to understand the neurobiological mechanisms by
which ketamine could produce such a rapid and efficacious response, and my
laboratory initiated studies to address this question. The hope was that this
information could also provide novel targets for the development of new medications.

The
initial question was how ketamine, an antagonist of the excitatory
neurotransmitter glutamate at the NMDA receptors, which causes transient
psychotic and dissociative effects, could produce a subsequent rapid and
sustained antidepressant response? Early studies reported that while ketamine
blocks NMDA receptors; it produces a paradoxical increase in brain levels of
glutamate, the neurotransmitter that excites NMDA receptors. Subsequent studies
found that low doses of ketamine selectively block NMDA receptors on tonic
firing GABA (gamma-aminobutyric acid) inhibitory neurons because these neurons
are tonically firing, which leads to the open channel state that ketamine can
access. The reduced activity of the interneurons then results in disinhibition
of excitatory neurons, thereby explaining the burst of glutamate.
Interestingly, the burst is rapid and transient, and correlates with the time
period for the initial psychotic and dissociative effects observed after
dosing, when brain levels of ketamine are highest.

But
how might this burst of glutamate translate into an antidepressant response?
Cellular models of learning and memory demonstrate that stimulation of
glutamate neurotransmission and activation of another major class of receptors,
referred to as AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid) receptors, together with NMDA
receptors increases the number of synaptic connections on excitatory neurons,
which is thought to contribute to long-term memory. We and others in the field
reasoned that ketamine, via this glutamate burst, could increase synaptic
connections in brain regions known to undergo atrophy and loss of synapses in
animals exposed to chronic stress and in depressed patients.8
(Exposing rodents to chronic or traumatic stress, which is known to precipitate
or exacerbate depressive-like symptoms, decreases synaptic connections in the
hippocampus and prefrontal cortex, two brain regions implicated in depression
neurobiology. In addition, brain imaging studies have consistently reported a reduction
in the size of the hippocampus and prefrontal cortex in depressed patients, and
postmortem studies report a reduction of synapse numbers in the brains of
depressed subjects.)

In
animal studies in collaboration with George Aghajanian and Rong-Jian Liu at
Yale, we tested the effects of ketamine on synapses in excitatory neurons of
the prefrontal cortex. The results were astounding: a single dose of ketamine
rapidly increased the number and function of these synapses.9 This
was determined by recording responses from individual neurons in brain slices
from animals previously administered ketamine. In addition, neurons were filled
with a dye to label neuronal processes, allowing measurement of the number and
size of spines where synapses are found. These studies demonstrated that a
single dose of ketamine increased the amplitude and frequency of postsynaptic
currents in pyramidal neurons, and that this effect was associated with an
increase in the number and size of spine synapses.

Analysis
of synaptic proteins that make up the spines demonstrated, further, that this
increase in number occurred as early as two hours after a single dose of
ketamine, consistent with the time course of its therapeutic actions. We also
found that a single dose of ketamine rapidly reversed the synaptic deficits
caused by chronic stress exposure, whichcorrelated with reduction in behavioral abnormalities, notably anhedonia
(the inability to experience pleasure) and helpless behaviors.10

Subsequent
studies of the molecular and cellular mechanisms underlying the actions of
ketamine have demonstrated a role for the rapid release of BDNF, and for
activation of the mTORC1 signaling pathway known to be important for the
synthesis of synaptic proteinsrequired
for long-term memory. Questions still remain regarding the initial cellular
process triggered by ketamine: notably, is the glutamate burst resulting from
ketamine blockade of NMDA receptors on interneurons the key cellular trigger or
do the antidepressant actions of ketamine result from blockade of NMDA
receptors on excitatory neurons? Studies are ongoing to selectively delete NMDA
receptors on the GABA versus glutamate neurons to test these two possibilities,
and could provide insight for identifying new targets on these neuronal
populations for future drug development.

Novel
Classes of Ketamine-Like Agents

The
psychotomimetic and dissociative effects of ketamine, and its attendant abuse
potential, have stimulated the search for novel agents with the drug’s rapid
and efficacious antidepressant actions but without these side effects. An early
study demonstrated that an antagonist selective for the GluN2B subunit of the
NMDA receptor, CP101,606, also produced an antidepressant response after a
single dose.11 Although some mild side effects were observed, this
report led to studies of other GluN2B selective antagonists in rodent models,
with similar findings. Clinical trials with selective GluN2B agents in
depressed patients have reported mixed results, and additional studies are
needed to further test this possible target.

There
have also been efforts to develop the stereoisomers and metabolites of ketamine
as rapid antidepressants, some also with the potential of fewer side effects.
The initial ketamine studies discussed above were conducted with a mixture of
both stereoisomers [(R,S)-ketamine], but more recent work has examined the
actions of each stereoisomer alone. (S)-ketamine has three- to four-fold higher
affinity for the NMDA receptor than (R)-ketamine, and a nasal application,
referred to as esketamine, is undergoing development by Johnson & Johnson
for the treatment of depression and suicide ideation.12 Initial
clinical studies have been promising, and the nasal application provides a less
expensive, much more accessible mode of administration that can be delivered in
a doctor’s office compared to the intravenous route in a hospital setting used
in studies of (R,S)-ketamine. Esketamine has received “breakthrough therapy”
status from the Food & Drug Administration (FDA), which means that it will
be fast tracked for approval, even though it appears to have the same side
effects as (R,S)-ketamine.

Studies
in rodent models have reported that (R)-ketamine also has antidepressant
effects but without the behavioral actions that predict (R,S)-ketamine’s side
effects (i.e., decreased sensory motor gating behavior, and increased
conditioned place preference, a measure of the motivational effects of drugs of
abuse ).13 However, there have been no clinical trials to date demonstrating
(R)-ketamine’s efficacy. A major ketamine metabolite,
(2R,6R)-hydroxynorketamine, is also reported to have antidepressant actions in
rodent models without the behavioral side effects of (R,S)-ketamine.14
Moreover, this compound’s antidepressant actions were independent of effects at
the NMDA receptor, indicating a potential novel mechanism of action. Efforts
are currently underway to test the efficacy of this metabolite in depressed
patients.

Another
interesting agent under development is GLYX-13, or Rapastinel, which
purportedly acts as a glycine-like partial agonist of the NMDA receptor.
Activation of the NMDA receptor complex and channel opening requires both
glycine and glutamate, which function as co-activators, and Rapastinel acts in
a manner similar to glycine to co-activate the NMDA receptor. The drug is a
tetrapeptide developed by Joseph Moskal, a professor of biomedical engineering
at Northwestern University; his work led to studies demonstrating that
Rapastinel produces rapid and long-lasting antidepressant actions in rodent
models, but without the behavioral side effect profile of ketamine.15
There have also been preliminary reports on the clinical efficacy of Rapastinel
in depressed patients. Together, these results led to a startup company,
Naurex, headed by Moskal. Allergan subsequently acquired Naurex and is
currently conducting phase III trials of Rapastinel, which like esketamine, has
received “breakthrough” status from the FDA.

A
Bright Future for Pharmacotherapies

Patients
who are unresponsive to typical antidepressant agents have begun seeking out
treatment centers that offer ketamine, even though they may find the
dissociative and psychotomimetic side effects unpleasant; in fact, many
continue receiving treatments on a weekly to monthly basis, even after
particularly difficult experiences. Patients often find ketamine treatment via
pain clinics that offer the drug for chronic neuropathic pain, because of the
lack of availability in hospitals or psychiatry clinics. But that is starting
to change. Yale New Haven Hospital, as well as other centers around the
country, are now offering ketamine as an outpatient therapy, and insurance
companies are beginning to cover these treatments, understanding the importance
of treating patients before they must be hospitalized (e.g., those at risk of
suicide). However, it is important to remember that ketamine is a drug of abuse
and that the potential adverse effects of long-term use have not been studied.

Investigations
into ketamine’s novel mechanism of action, including blockade of NMDA
receptors, glutamate burst, and rapid induction of synaptic connections that
reverses the deficits of stress and depression, have reinvigorated research
efforts to identify additional rapid-acting glutamatergic antidepressants with
reduced side effects. While further studies are needed to more fully elucidate
the neurobiological effects underlying ketamine’s efficacy against depression,
the field is poised for major advances in the treatment of this debilitating
illness.